The Mechanics of Morphogenesis

Dear Min and Xingbo, I am putting in a proposal this summer to the Pew Foundation. I want to put something regarding cell mechanics. Most likely, something that synthesizes both your work (and some new 3D worm stuff) into a single meaningful research plan. I would like some help with this, mainly because its you two that are thinking the hardest about these problems. I am going to start sketching out an outline, which we can then fill in as time goes on. Please provide me feedback as I am writing this.

Diversity of size and shape of organs during morphogenesis: Wings of dipterans illustrate marked differences in the size and shape of organs. Variations in wing length can almost reach tenfold (left). The width-to-length ratio can also vary significantly (right). Scale bar, 1 mm. (Ref:Legoff Lecuit Nature.)

Despite decades of study into the molecular mechanisms of morphogenesis, we still lack a single mechanistic framework within which to understand the patterning signals and cellular responses that are coordinated in growing and remodeling tissues. Understanding how tissues are shaped and organs are made requires understanding the orchestration of the elementary cellular processes of cell division, cell death, cell shape changes, and cell rearrangements. While we have extensive knowledge of the tissue-specific set of signaling molecules, growth factors, that promote cell division and regulate tissue size, and the proteins involved in converting chemical energy into work, molecular motors, we lack an understanding of how these molecular components coordinate cellular processes in developing tissues. In some senses we are still far from realizing d’Arcy Thompson’s dream of understanding Growth and Form – a central and fundamental problem in biology.

Manifestly, mechanical forces play a central role in the emergence of organismal form, and are a consequence of developmentally patterned cellular expression states. In particular, forces are generated by molecular motors and transmitted via cytoskeletal elements and adhesion molecules within and between cells. That said, in the context of a tissue, mechanical stresses are fundamentally distinct from any other property, or field, in that they are a collective property of the whole rather than an intrinsic cellular property. Going beyond their role in generating cellular motion, in recent years, mechanical forces have been ascribed a key regulatory roles in influencing growth, determining the axis of cell division, and stem-cell differentiation. Owing to their collective property, mechanical forces therefore have the potential to coordinate growth and form at the multicellular scales of tissues and organs.

Focused on the Mechanics of Morphogenesis, research in my group comprises data-analysis and modeling efforts conducted in very close collaboration with experimentalists. In particular, my group is focused on 1) developing model-driven non-invasive image analysis tools that permit the first invivo measurements of mechanical forces, and to link them to the cellular and biochemical processes by which they are generated, propagated, and received within the organism, and 2) to integrate the roles of mechanical forces in tissue morphogenesis and patterning with the of understanding how physical and chemical patterning is realized during the course of organismal development. Below I describe two ongoing projects focused on morphogenesis in the Drosophila embryo and pupa, and a third new research direction focused on early embryonic development in the c elegans.

Memories in cellular flows, and their role in morphogenesis in the scutellum of the Drosophila pupa

Central question (a first guess): How does a developmentally patterned stress field generate a complex flow of cells?

[MIN, I would like if you can have a crack at writing 2-3 paragraphs on this project. Make sure to include a figure with a few panels that you think captures the essence of you work and perspective. In some senses, the readers will basically only really see your figure. So try to distill all your thoughts into a few panels in a single figure. The words should just support the figure.]

What I see as the main points to highlight: 1) The flow is complex 2) Heterogeneous Fat-Ds pathway activity generates active stresses in localized regions of the tissue, pulling/pushing other regions. 3) We need to be able to measure stresses, and demark the active and passive regions of the flow, and 4) Fat pathway activity generates stresses, that produce flows, that advects Fat pathway activity as well as the stress state – what are the consequences of this? This somehow needs to be tied together into a single question. I obviously think its memory. It would be great if we could talk about the new measurement of stress as well.